1. Technical Field
The present invention relates to monoclonal antibodies, and more specifically, to monoclonal antibodies that specifically recognize platelet GPIbα. These antibodies are useful, for instance, in antithrombotic therapy and in diagnostics, as well as in animal models of thrombosis, hemostasis, thrombocytopenia, and anti-angiogenesis.
2. Description of the Related Art
Platelet adhesion and aggregation are key events required to arrest bleeding. However, the same processes also contribute to the generation of thrombi within atherosclerotic arteries such as the coronary or cerebral arteries, which is the worldwide leading cause of morbidity and mortality.
Platelet GPIbα is an important platelet receptor which mediates platelet adhesion to the vessel wall by interacting with, for example, the von Willebrand factor (Wolfgang et al., 2006, PNAS, 103:16900-16905). Once a platelet is anchored to the vessel wall, it facilitates the aggregation of other platelets (Ni H et al. 2003 Transfus Apher Sci. 28: 257-64 and Wolfgang et al., 2006, PNAS, 103:16900-16905). Since GPIbα is involved in the early stages of thrombosis, antagonists of platelet GPIbα have a great potential for anti-thrombotic therapy and could prevent vessel occlusion. Currently, there is no therapy in the market that specifically targets GPIbα.
Antagonists targeting GPIbα would provide significant advantages as compared with other anti-platelet drugs such as those antagonists to β3 integrin (also known as GPIIbIIIa), such as ReoPro™ approved 1994, Integrinlin™ approved 1998, Aggrastat™ approved 1998, already in the market. The prevailing view is that antagonists of GPIbα may prevent the thrombus formation at an earlier stage than β3 integrin antagonists, and as such would be more potent and would exhibit less side effects than β3 antagonists (e.g., bleed tendency observed in antagonists to the GPIIbIIIa receptor).
Monoclonal antibodies against GPIbα are readily available and currently used in the art. However, these antibodies have been made in wild-type animals (e.g., mice) and, as such, do not recognize the mouse GPIbα. Since mouse and human GPIbα are similar polypeptides (e.g., they possess an important degree of homology), the use of a wild-type mouse to generate the monoclonal antibodies limits the repertoire of the antibodies produced to epitopes present on the human GPIbα and absent on the mouse GPIbα.
In light of the above, it would be highly desirable to be provided with antibodies or compositions derived therefrom capable of specifically recognizing the platelet GPIbα receptor. Those agents would preferably specifically recognize both the human and the mouse GPIbα receptors on platelets. Those agents are preferably antibodies, such as monoclonal antibodies, capable of specifically recognizing and/or neutralizing the platelet GPIbα receptor.